tbuckley/cabot-search huggingface dataset:
Pembrolizumab (pembro) plus binimetinib (bini) with or without chemotherapy (chemo) for metastatic colorectal cancer (mCRC): Results from KEYNOTE-651 cohorts A, C, and E.
Authors: Eric Xueyu Chen, Petr Kavan, Mustapha Tehfe, Jeremy S. Kortmansky, Michael B. Sawyer, E. Gabriela Chiorean, Christopher Hanyoung Lieu, Blase N. Polite, Lucas Wong, Marwan Fakih, Kristen Renee Spencer, Jorge Chaves, Chenxiang Li, David Carpenter, Pierre Leconte, Richard D. Kim
Journal: Journal of Clinical Oncology (2022)

3573 Background: Response to antiPD-1 monotherapy is poor in microsatellite stable (MSS)/mismatch-repair proficient (pMMR) mCRC; the combination of antiPD-1 pembro + anti-MEK bini, with or without chemo, may improve upon this limited response. KEYNOTE-651 (NCT03374254) is an open-label phase 1b multicenter trial of pembro + bini (cohort A) or pembro + bini + chemo (mFOLFOX7 in cohort C, FOLFIRI in cohort E) in MSS/pMMR mCRC. Preliminary results from the dose-finding phase at 2 dose levels (DL) of bini are presented. Methods: Patients (pts) had MSS/pMMR mCRC and must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin in cohort A, or with fluoropyrimidine + oxaliplatin-based regimen in cohort E; pts were previously untreated in cohort C. Pts received pembro 200 mg Q3W + bini 30 mg BID (cohort A, DL1), pembro 200 mg Q3W+ bini 30 mg BID + mFOLFOX7 Q2W (cohort C, DL1) or pembro 200 mg Q3W + bini 30 mg BID + FOLFIRI Q2W (cohort E, DL1). Bini dose escalation to 45 mg BID (DL2) was planned in cohorts A, C, and E, with a target dose-limiting toxicity (DLT) of 30%. Primary end point was safety (DLT). Secondary end point was ORR. DCR, PFS, and OS were exploratory. ORR, DCR, and PFS were assessed by investigator per RECIST v1.1. Results: Median study follow-up at data cutoff (Oct 15, 2021) was 36 mo (range, 32-43) for cohort A, 17 mo (2-24) for cohort C, and 11 mo (2-25) for cohort E. In cohort A, 1/6 pts (17%) had DLT at DL1; no DLT occurred in 14 pts (0%) at DL2. In cohort A, gr 3/4 TRAEs occurred in 3/6 pts (50%) at DL1 and 8/14 pts (57%) at DL2. In cohort C, 3/9 evaluable pts (33%) had DLT at DL1; thus, bini dose was not escalated to DL2. In cohort C, gr 3/4 TRAEs occurred in 9/11 total pts (82%). In cohort E, 1/5 evaluable pts (20%) had DLT at DL1 and 5/10 evaluable pts (50%) had DLT at DL2. Enrollment was stopped in cohort E, DL2 and bini dose was de-escalated to DL1; 2/4 additional pts (50%) had DLT at DL1 (total 3/9 pts [33%] had DLT in cohort E, DL1). In cohort E, gr 3/4 TRAEs occurred in 5/9 pts (56%) at DL1 and 10/11 total pts (91%) at DL2. No gr 5 TRAEs occurred in any cohort. ORR was 0% in cohort A; limited efficacy was seen in cohorts C and E (Table). Conclusions: Bini could be safely combined with pembro in cohort A. However, with bini + pembro + chemo, the 45-mg dose of bini was not well tolerated and required dose reduction to 30 mg. Addition of bini to pembro + chemo did not improve efficacy; therefore, enrollment was prematurely closed in cohorts C and E. Efficacy by KRAS mutation status will be shown. Clinical trial information: NCT03374254. [Table: see text]
Automated H&amp;E whole slide image surrogate Ki67 index prediction and prognostic value across breast cancer subtypes.
Authors: Satabhisa Mukhopadhyay, Tathagata Dasgupta, Angelene Berwick, Elizabeth Walsh, Andrew Hanby, Rebecca Millican-Slater, Michele Cummings, Nicolas M. Orsi
Journal: Journal of Clinical Oncology (2022)

e12518 Background: Despite its purported prognostic significance in breast cancer, Ki67 index assessment remains poorly standardized and features high discordance rates amongst pathologists. Moreover, its clinical utility is presently confined to low stage, ER+/HER2- tumors in determining the advisability of adjuvant chemotherapy. Unfortunately, established cut-offs limit its utility to tumors with either high or low Ki67 index extremes. While Ki67 is a marker of actively dividing cells, it fails to capture the detail of cell cycle phase and dynamics which could be informative in terms of prognosis and tumor sensitivity to specific therapies (e.g. CDK4/6 inhibitors). This study therefore developed two novel indices as surrogates of (i) Ki67 index and (ii) quiescent cell population load (QPL). Methods: Breast cancer (comprising evenly distributed hormone receptor/HER2 status cases) H&amp;E slides ( n = 79 cases/108 slides) were digitized on an Aperio DT3 scanner, and used to extract surrogate Ki67 and QPL indices. Sections were also stained for Ki67 by immunohistochemistry (IHC) using a clinically validated assay and digitized. Whole slide image (WSI) tumor Ki67 counts were performed on QuPath and used to validate the surrogate Ki67 index (Cohen’s kappa score). Indices (i) and (ii) were related to progression free survival (PFS). Survival analyses were performed using Kaplan-Meier (KM; with median cut-off) and Cox Proportional Hazards (as a continuous variable) models. Results: The surrogate Ki67 index showed good concordance with IHC scores (kappa = 0.76; 95%CI 0.61-0.91; P&lt; 0.00001). However, this surrogate index performed better as a prognostic indicator of PFS compared to conventional Ki67 IHC (KM P = 0.048; HR = 1.35, P = 0.015 vs. KM P = 0.70; HR = 1.23, P = 0.08). Prognostically, the QPL index outperformed both Ki67 indices (KM P = 0.03; HR = 3.22, P = 0.001). Conclusions: We have developed two novel surrogate indices of Ki67 and QPL that can be readily automated to analyze H&amp;E breast cancer WSIs. Our results show that both outperformed conventional Ki67 IHC evaluation in terms of prognostication, applied across molecular subtypes, improved informativeness of mid-range Ki67 index calls, and could potentially have predictive merit in selecting patients for cell cycle targeted therapies such as CDK4/6 inhibitors.
What is the optimal management of nodal oligorecurrent prostate cancer? Results from a large series of patients treated with salvage lymph node dissection
Authors: N. Fossati, R.J. Karnes, A. Heidenreich, A. Kretschmer, A. Buchner, C. Stief, S. Joniau, H. Van Poppel, D. Osmonov, D. Pfister, K-P. Juenemann, S. Shariat, A. Hiester, P. Albers, D. Tilki, M. Graefen, I.S. Gill, A. Mottrie, G. Gandaglia, A. Gallina, F. Montorsi, A. Briganti
Journal: European Urology (2022)
ATR-mediated CD47 and PD-L1 up-regulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer
Authors: Rodney Cheng-En Hsieh, Sunil Krishnan, Ren-Chin Wu, Akash R. Boda, Arthur Liu, Michelle Winkler, Wen-Hao Hsu, Steven Hsesheng Lin, Mien-Chie Hung, Li-Chuan Chan, Krithikaa Rajkumar Bhanu, Anupallavi Srinivasamani, Ricardo Alexandre De Azevedo, Yung-Chih Chou, Ronald A. DePinho, Matthew Gubin, Eduardo Vilar, Chao Hsien Chen, Ravaen Slay, Priyamvada Jayaprakash, Shweta Mahendra Hegde, Genevieve Hartley, Spencer T. Lea, Rishika Prasad, Brittany Morrow, Coline Agnes Couillault, Madeline Steiner, Chun-Chieh Wang, Bhanu Prasad Venkatesulu, Cullen Taniguchi, Yon Son Betty Kim, Junjie Chen, Nils-Petter Rudqvist, Michael A. Curran
Journal: Science Immunology (2022)

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.
KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target
Authors: Morgane Cheminant, Ludovic Lhermitte, Julie Bruneau, Hélène Sicard, Cécile Bonnafous, Aurore Touzart, Estelle Bourbon, Nicolas Ortonne, Laurent Genestier, Philippe Gaulard, Patricia Palmic, Felipe Suarez, Laurent Frenzel, Louise Naveau, Ali Bazarbachi, Mickaël Dussiot, Laetitia Waast, Véronique Avettand-Fenoel, Chantal Brouzes, Claudine Pique, Yves Lepelletier, Vahid Asnafi, Ambroise Marçais, Olivier Hermine
Journal: Blood (2022)
Conditional survival of patients with low-risk prostate cancer: Temporal changes in active surveillance permanence according to risk stratification
Authors: F. Mistretta, S. Luzzago, M.L. Piccinelli, S. Alessi, G. Cozzi, A. Cioffi, M. Fontana, D. Bottero, G. Marvaso, M. Ferro, D.V. Matei, B.A. Jereczek Fossa, G. Petralia, G. Musi, O. De Cobelli
Journal: European Urology (2022)
HGG-17. Novel Fusion in Congenital Brainstem Diffuse High-Grade Glioma
Authors: Gregory Norris, Andrew Donson, Sarah Milgrom, Alisa Gaskell, Nicholas Willard, Nicholas Foreman, Ahmed Gilani, Nathan Dahl
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Infant-type hemispheric glioma, previously termed infantile glioblastoma multiforme, is a rare infantile neoplasm with improved survival and distinct molecular features when compared to other pediatric and adult-type high-grade glioma. Infant-type high-grade gliomas are typically located in the cerebral hemispheres and are characterized by ALK, ROS1, MET, and NTRK fusions. Typical brainstem gliomas (diffuse midline glioma, H3 K27-altered or diffuse intrinsic pontine glioma) are comparatively rare in this age group. As a result, the biology of brainstem congenital high-grade gliomas is poorly described. RESULTS: A 3 month old female who initially presented with failure to thrive had an apneic event and was found to have an infiltrative mass in the medulla with expansion into the pons and cervical spine on magnetic resonance imaging. She underwent surgical biopsy with pathology revealing diffuse high-grade glioma, WHO grade 4. Next generation sequencing showed no alterations to H3F3A, IDH, or fusions involving BRAF, ALK, ROS1, MET, or NTRK. Whole-transcriptome sequencing revealed a novel fusion of PDGFRB:APOBEC3C. She received chemotherapy with 2 cycles of carboplatin/etoposide and 2 cycles of carboplatin/etoposide/imatinib before having disease progression. She then underwent palliative radiation (35 Gy in 10 fractions) with near complete regression of her disease. Surprisingly, our patient has not had any progression of disease or new lesions now two years from her last therapy. CONCLUSION: Congenital high-grade glioma is a rare, unique entity that greatly differs from its adult and childhood counterparts. Here, we discuss a previously-unreported fusion of PDGFB:APOBEC3C in a patient with congenital brainstem diffuse high-grade glioma with a favorable clinical course. This highlights the importance of routine molecular characterization, both to better understand the complex biology of this rare disease and to guide prognosis and clinical decision making for individual patients and families.
DIPG-45. Radiation induces a robust interferon response in Diffuse Midline Glioma (DMG), improving the potential for combination immunotherapy
Authors: Hanna E Minns, Oscar Padilla, Hong-Jian Wei, Andrea Webster-Carrion, Masih Tazhibi, Nicholas McQuillan, Xu Zhang, Rebecca Yeh, Zhiguo Zhang, Luca Szalontay, Jovana Pavisic, Guy Garty, James Garvin, Stergios Zacharoulis, Peter Canoll, Claire I Vanpouille-Box, Vilas Menon, Marta Olah, Raul Rabadan, Cheng-Chia Wu, Robyn D Gartrell
Journal: Neuro-Oncology (2022)

Abstract Diffuse Midline Glioma (DMG), H3K27M altered, confers a dismal survival of 9-15 months and has a non-inflammatory tumor immune microenvironment (TIME). Radiation therapy (RT) is the mainstay treatment for DMG and has been shown in other cancers to recruit an immune component. However, the effect of RT on the DMG TIME has not been explored. In a syngeneic murine model of pontine DMG (PDGFB+, H3.3K27M, p53−/−), mice were treated with single fraction 15Gy RT or sham control, four mice per group. We performed single cell sequencing after CD45 isolation to evaluate the TIME 4 days post RT and compare to untreated tumor (sham control). Unsupervised clustering of 14,848 CD45+ cells revealed 16 immune cell subsets, most abundantly microglia at 75% of cells, with four subtypes representing a spectrum of homeostatic to activated. Microglia from RT are more concentrated in the activated subtypes with an upregulation of interferon response (i.e. Isg15, Ifit3) compared to untreated tumor with an increase in several interferon pathways using REACTOME. Consistent with RT response, RT treated tumors have increase in cell cycle regulatory genes such as Cdkn1a, across all clusters. In non-resident myeloid cells, compared to untreated tumor, RT is associated with a robust upregulation of interferon response genes in both macrophages (Isg15 Fold Change (FC) 2.30; Ifit1 FC 1.64; Ifit3 FC 2.02; Cxcl10 FC 2.29) and dendritic cells (Isg15 FC 2.67; Ifit1 FC 1.72; Ifit3 FC 2.06; Cxcl10 FC 1.50). We also find differential expression of immune checkpoints in RT-treated versus untreated tumor with decreased expression of Lag3, Tim3 (Havcr2), and Csf1R and increased expression of Cd47, Sirpa and Gitr (Tnfrsf18) post RT. In summary, RT stimulates a pro-inflammatory TIME response and alters immune checkpoints in DMG, highlighting the potential for combining RT and immunotherapy in these tumors.
The clinical implications of TMB and the relationship between TMB and EGFR mutations in non-small cell lung cancer of Xuanwei, China.
Authors: Hao Peng, Hushan Zhang, Libin Zhang, Zheyuan Xu, Yang Wang, Han Wang
Journal: Journal of Clinical Oncology (2022)

e20512 Background: Xuanwei lung cancer is a type of non-small cell lung cancer that occurs in Xuanwei, southwest China. It is different from non-Xuanwei non-small cell lung cancer in many aspects. The key is that Xuanwei lung cancer does not currently have a recognized prognostic biomarker. The significant molecular difference between Xuanwei lung cancer and non-Xuanwei lung cancer is the mutation type and mutation ratio of EGFR. Are different mutations of EGFR related to the prognosis of Xuanwei lung cancer? What are the reasons for the difference between Xuanwei lung cancer and non-Xuanwei lung cancer? These are clinical issues that we are very interested in. In addition, tumor mutation burden (TMB) has been shown to be an effective biomarker for predicting the clinical outcome of multiple cancer types. However, its prognostic value in Xuanwei lung cancer remains unknown. Methods: The Formalin-Fixed Paraffin-Embedded (FFPE) tissues samples from 172 primary NSCLC patients who have underwent next-generation sequencing (NGS) in a laboratory accredited by the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendment (CLIA) (3D Medicines Inc., Shanghai, China) from June 2015 to October 2020 were analyzed. The written informed consent was obtained from all included patients. The postoperative follow-up data of all these NSCLC patients were collected. Results: The prognosis of Xuanwei lung cancer is better than that of non-Xuanwei (p &lt; 0.05). Xuanwei is superior to non-Xuanwei mainly in EGFR-positive patients (p &lt; 0.05). Among patients without EGFR mutations, there is no difference in the prognosis of Xuanwei lung cancer and non-Xuanwei lung cancer. Further analysis revealed that there is a difference in TMB levels between Xuanwei lung cancer and non-Xuanwei lung cancer. The TMB level in Xuanwei lung cancer is significantly higher than that in non-Xuanwei lung cancer (p &lt; 0.05). EGFR mutations can be used as prognostic markers for Xuanwei lung cancer, and this is related to patients with EGFR mutations having higher TMB levels. Our research results indicate that EGFR mutation may help combine traditional clinicopathological risk factors to optimize risk stratification and guide treatment decisions. Conclusions: Xuanwei lung cancer is a special subtype of NSCLC with different molecular features and prognosis. Analysis of data in this area will lead to the development of precision treatment options for Xuanwei lung cancer.
Anal Cancer: Emerging Standards in a Rare Disease
Authors: Cathy Eng, Kristen K. Ciombor, May Cho, Jennifer A. Dorth, Lakshmi N. Rajdev, David P. Horowitz, Marc J. Gollub, Alexandre A. Jácome, Natalie A. Lockney, Roberta L. Muldoon, Mary Kay Washington, Brittany A. O'Brian, Amala Benny, Cody M. Lebeck Lee, Al B. Benson, Karyn A. Goodman, Van Karlyle Morris
Journal: Journal of Clinical Oncology (2022)

The social stigma surrounding an anal cancer diagnosis has traditionally prevented open discussions about this disease. However, as recent treatment options and an increasing rate of diagnoses are made worldwide, awareness is growing. In the United States alone, 9,090 individuals were expected to be diagnosed with anal cancer in 2021. The US annual incidence of squamous cell carcinoma of the anus continues to increase by 2.7% yearly, whereas the mortality rate increases by 3.1%. The main risk factor for anal cancer is a human papillomavirus infection; those with chronic immunosuppression are also at risk. Patients with HIV are 19 times more likely to develop anal cancer compared with the general population. In this review, we have provided an overview of the carcinoma of the anal canal, the role of screening, advancements in radiation therapy, and current trials investigating acute and chronic treatment-related toxicities. This article is a comprehensive approach to presenting the existing data in an effort to encourage continuous international interest in anal cancer.
GCT-13. KRAS MUTATION IN PEDIATRIC INTRACRANIAL GERM CELL TUMORS
Authors: Chusana Khaiman, Piti Techavichit, Chinachote Teerapakpinyo, Shanop Shuangshoti
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Intracranial germ cell tumors (IGCTs) are rare, highly curable neoplasms. KRAS is a gene in the KIT/RAS signaling pathway, and KRAS mutations were reported in patients diagnosed with IGCTs. OBJECTIVES: To describe clinicopathologic, molecular features of KRAS mutation and treatment outcome of children diagnosed with IGCTs. METHODS: A retrospective review in patients diagnosed with IGCTs at Department of Pediatrics, King Chulalongkorn Memorial Hospital from 2007 to 2019. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue for the molecular study. Identifies mutations in codon 12,13 and 61 of the KRAS gene was performed by using the real-time PCR technique of the Cobas® test and pyrosequencing method. RESULTS: Eighteen patients were diagnosed with IGCTs (11 males and seven females). Age ranged from 5 to 14 years (median 10.5 years). The diagnosis was germinoma and non-germinomatous IGCTs in 9 patients each. Elevated markers were revealed in approximately 25% of patients. Four patients (2 patients with germinoma and 2 with non-germinomatous IGCTs) had leptomeningeal involvement. All patients underwent tumor biopsy and received neoadjuvant chemotherapy. Radiotherapy was given in 16 patients and craniospinal radiation (CSI) was given only in leptomeningeal metastasis. With the median follow-up of 26 months, overall survival is 88.9% in germinomas and 37% in non-germinomatous IGCTs. Mutation of the KRAS gene was detected by pyrosequencing technique in one patient. The mutation located at codon 61, frequency 38.3% units, nucleotide substitution CAA &amp;gt; CTA and amino acid substitution was Q61L. The patient who carries mutant gene was diagnosed germinomatous germinoma with CSF metastasis and eventually died from treatment-related toxicity. CONCLUSIONS: Our study revealed treatment outcomes of IGCTs in Thai children. We describe KRAS codon 61 mutation in metastasis germinoma patients with poor outcome, support KRAS codon 61 mutation (Q61L) may have a clinical correlation in IGCTs.
Commentary: Indirect action pattern: A remote and cross-organ pharmacological mechanism for drug innovation
Authors: Yuan Gao, Jia-bo Wang
Journal: Acta Pharmaceutica Sinica B (2022)

The research and development (R&D) of innovative drugs is limited by the low success rates and high attrition of drug candidates, representing an unmet demand for healthy life. A methodological breakthrough of new drug R&D may breed acceleration. In the current issue, Clemens et al. reported a novel indirect action pattern of phosphatidic acid (PA) in an acetaminophen (APAP)-induced liver toxicity model. In this model, PA acted on a remote tissue – epididymal white adipose tissue (eWAT) firstly, and then induced eWAT-derived interlukin-6 as intermediate substance (IMS) to protect against APAP-induced liver injury, while had no effect on the primary disease site–liver. Of note, several recent studies also suggested that besides the conventional methodology of directly targeting the disease primary organ/site, utilizing endogenous substances (e.g., cytokines, microRNA, functional metabolites, or hormones) as IMS to achieve therapeutic purpose should also be considered during new drugs R&D, which we call it indirect action (INDA) here. Taking together, a fundamental breakthrough may be achieved when exploring the new drug R&D methodology from the perspective of INDA, indicating a potential strategy for drug innovation.